Contact Information: Michael D. Huband, B.S. In vitro Activity of Omadacycline and Comparators against Gram-Negative Bacterial Isolates Collected from Patients JMI Laboratories ECCMID 2017 345 Beaver Kreek Centre, Suite A in European Medical Centres (2016): Results from the SENTRY Antimicrobial Surveillance Program North Liberty, IA 52317 Poster #P1253 MD Huband, PR Rhomberg, HS Sader, JE Schuchert, RK Flamm Phone: (319) 665-3370 Fax: (319) 665-3371 JMI Laboratories, North Liberty, Iowa, USA Email: [email protected] REVISED ABSTRACT • This study evaluated the in vitro antibacterial activity of omadacycline and Figure 1 Cumulative % inhibition results for omadacycline and comparators Table 3 In vitro activity of omadacycline and comparators against gram- • The in vitro activity of omadacycline and comparator compounds against comparators against gram-negative bacterial isolates collected from patients against 4,019 Enterobacteriaceae isolates collected in European medical negative isolates collected from patients in European medical centres Enterobacteriaceae, nonfermenters, and fastidious gram-negative isolates Background: Omadacycline is a broad-spectrum aminomethylcycline of the with multiple infection types in European medical centres participating in the centres during 2016 during 2016 are presented in Table 3. Omadacycline (MIC50/90 1/8 mg/L) was ≥2-fold more Organism (no. tested) MIC MIC CLSIa EUCASTa tetracycline family in late-stage clinical development for community-acquired 2016 SENTRY surveillance program 50 90 active than doxycycline (MIC50/90 2/>8 mg/L; 66.3% susceptible [CLSI criteria]) 100 antimicrobial agent (mg/L) (mg/L) %S %I %R %S %I %R bacterial pneumonia and acute bacterial skin and skin structure infections b and tetracycline (MIC 2/>16 mg/L; 60.1% susceptible [CLSI criteria]) and MIC90 (mg/L) 92.3 Enterobacteriaceae (4,019) 50/90 (intravenous and oral formulations). Omadacycline has shown potent in vitro 90 87.1 Omadacycline 1 8 — — — — — — four- to eight-fold less active than tigecycline (MIC , 0.25/1 mg/L; 92.5% Doxycycline 2 >8 66.3 9.6 24.1 — — — 50/90 Doxycycline 77.4 75.9 activity against key bacterial pathogens, including gram-negative bacterial 80 Tetracycline 2 >16 60.1 3.1 36.8 — — — susceptible [EUCAST]) against Enterobacteriaceae Materials AND METHODS c Tetracycline 66.3 Tigecycline 0.25 1 97.8 2.1 0.1 92.5 5.3 2.2 isolates expressing resistance to β-lactams, fluoroquinolones, and/or common 70 63.2 Omadacycline 58.7 60.1 Levofloxacin 0.06 >4 73.4 0.9 25.7 73.4 0.9 25.7 • Against A. baumannii isolates, omadacycline (MIC50/90, 4/8 mg/L; 64.6% tetracycline-resistance mechanisms. This study evaluated the in vitro antibacterial 60 56.5 55.0 Ceftazidime 0.25 >32 79.1 2.1 18.8 74.5 4.6 20.9 • A total of 4,987 gram-negative bacterial isolates composed of 315 Piperacillin-tazobactam 2 64 85.0 5.8 9.3 80.4 4.6 15.0 inhibited at ≤4 mg/L) was slightly less active than tigecycline (MIC50/90, activity of omadacycline and comparators against gram-negative bacterial isolates 50 Escherichia coli (1,849) Acinetobacter spp., 4,019 Enterobacteriaceae, 358 Haemophilus influenzae, 41.8 2/4 mg/L), whereas susceptibility to doxycycline (MIC50/90, >8/>8 mg/L; Omadacycline 1 2 — — — — — — collected from patients in European medical centres that participated in the 2016 40 33.9 162 Moraxella catarrhalis, and 133 Stenotrophomonas maltophilia were Doxycycline 2 >8 66.3 12.3 21.4 — — — 42.8% susceptible [CLSI]) and tetracycline (MIC50/90, >16/>16 mg/L; 17.8% SENTRY surveillance program. 30 26.7 Tetracycline 2 >16 60.6 0.3 39.2 — — — collected from patients with multiple infection types in 38 medical centres in c susceptible [CLSI]) was low (Tables 2 and 3) Cumulative % inhibition 20 Tigecycline 0.12 0.25 99.9 0.1 0.0 99.9 0.1 0.1 Methods: A total of 4,019 clinically significant Enterobacteriaceae, 358 Haemophilus 18 European countries and Israel during 2016. Only one isolate per patient/ 11.3 ESBL phenotype (422) • Omadacycline was active against S. maltophilia isolates, inhibiting 82.0% at Omadacycline 1 2 — — — — — — 10 3.3 4.3 influenzae, 162 Moraxella catarrhalis, and 297 Acinetobacter baumannii infection episode is represented 0.1 0.0 0.1 0.6 0.1 Doxycycline 8 >8 46.2 23.7 30.1 — — — ≤4 mg/L (Table 2) 0 calcoaceticus species complex (A. baumannii) isolates representing multiple 0.12 0.25 0.5 1 2 4 8 Tetracycline >16 >16 36.0 0.2 63.7 — — — • Bacterial isolates were initially identified by the submitting laboratories and Tigecycline 0.12 0.25 99.8 0.2 0.0c 99.8 0.0 0.2 • Haemophilus influenzae (including β-lactamase-producing strains) were infection types were collected during 2016. One isolate/patient/infection episode confirmed by JMI Laboratories using matrix-assisted laser desorption/ionization- MIC (mg/L) Klebsiella pneumoniae (830) inhibited by omadacycline, tetracycline, and tigecycline (MIC values 1, 1, and was included. Species identification confirmation and antimicrobial susceptibility Omadacycline 2 8 — — — — — — 90 time of flight mass spectrometry (Bruker Daltonics, Bremen, Germany) Doxycycline 2 >8 65.0 8.6 26.4 — — — 0.25 mg/L, respectively) (Table 3) testing was performed in a central laboratory according to reference (CLSI) broth Tetracycline 2 >16 63.1 4.7 32.2 — — — • Susceptibility testing was performed according to CLSI (M07-A10, 2015) Tigecycline 0.5 1 98.4 1.6 0.0c 93.4 5.1 1.6 • Moraxella catarrhalis isolates were inhibited by low levels of omadacycline microdilution methodology and results interpreted per EUCAST/CLSI breakpoints. ESBL phenotype (386) reference broth microdilution methodology, and results were interpreted Omadacycline 2 8 — — — — — — (MIC50/90, 0.25/0.25 mg/L; 100.0% susceptible at ≤0.5 mg/L), tetracycline Results: Gram-negative isolates were collected from bloodstream infection (BSI; using EUCAST (2017) breakpoint interpretive criteria. CLSI quality control Doxycycline 8 >8 44.0 14.8 41.2 — — — Tetracycline 16 >16 40.2 7.8 52.1 — — — (MIC50/90, 0.25/0.5 mg/L), and tigecycline (MIC50/90, 0.06/0.06 mg/L; Table 3) 30.4%), pneumonia in hospitalized patients (PIHP; 22.1%), urinary tract infection (QC) reference strains (M100-S27, 2017) were tested concurrently and • Omadacycline demonstrated good in vitro activity against Enterobacteriaceae Tigecycline 0.5 2 97.7 2.3 0.0c 89.4 8.3 2.3 (UTI; 16.5%), skin and skin structure infection (SSSI; 14.1%), intra-abdominal included Escherichia coli ATCC 25922, ATCC 35218 and NCTC 13353, K. oxytoca (192) isolates (MIC50/90 1/8 mg/L; 87.1% inhibited at ≤4 mg/L) and was most Omadacycline 1 2 — — — — — — infection (IAI; 7.5%), respiratory tract infection (RTI; 9.1%), and other infection Klebsiella pneumoniae ATCC 700603, ATCC BAA-1705 and ATCC BAA-2814, Doxycycline 1 4 92.1 3.7 4.2 — — — active against E. coli, E. coli exhibiting an ESBL phenotype, and Klebsiella Tetracycline 1 8 89.6 2.1 8.3 — — — types (0.3%). Against Enterobacteriaceae, omadacycline (MIC50/90 1/8 mg/L) was Haemophilus influenzae ATCC 49247 and ATCC 49766, and Pseudomonas oxytoca isolates (MIC values, 1/2 mg/L; Table 2). Omadacycline inhibited Tigecycline 0.25 0.5 100.0 0.0 0.0c 98.4 1.6 0.0 50/90 d very active, inhibiting 87.1% of isolates at ≤4 mg/L; corresponding susceptibilities Enterobacter cloacae (323) CONCLUSIONS aeruginosa ATCC 27853 93.8% of Enterobacter cloacae species complex (E. cloacae), 88.5% of Omadacycline 2 4 — — — — — — (EUCAST/CLSI) to levofloxacin, ceftazidime, piperacillin-tazobactam, and ceftazidime-nonsusceptible E. cloacae, 95.8% of Citrobacter spp., 86.6% of Doxycycline 2 8 83.9 7.7 8.4 — — — Tetracycline 2 >16 81.4 1.9 16.7 — — — • Omadacycline was active against Enterobacteriaceae isolates of multiple tetracycline were 73.4%/73.4%, 74.5%/79.1%, 80.4%/85.0%, and —/60.1%, K. pneumoniae, 76.9% of ESBL-phenotype K. pneumoniae, and 83.0% of Tigecycline 0.5 0.5 99.4 0.6 0.0c 94.4 5.0 0.6 respectively. Where treatment options may be limited, omadacycline remained Ceftazidime-nonsusceptible (87)e infection types, inhibiting 87.1% of all isolates tested at ≤4 mg/L results Serratia marcescens isolates at ≤4 mg/L (Table 2) Omadacycline 2 8 — — — — — — active against resistant organisms/groups, including ESBL phenotype Escherichia Doxycycline 4 >8 57.5 23.0 19.5 — — — • The in vitro spectrum of omadacycline included ESBL-phenotype isolates • Enterobacteriaceae susceptibilities (EUCAST/CLSI) to comparators composed Tetracycline 8 >16 46.0 4.6 49.4 — — — coli (MIC 1/2 mg/L) and Klebsiella pneumoniae (MIC 2/8 mg/L; 76.9% c of E. coli (MIC , 1/2 mg/L) and K. pneumoniae (MIC , 2/8 mg/L; 76.9% 50/90 50/90 • Overall, 15.7% of the Enterobacteriaceae isolates and 15.2% of the of levofloxacin, ceftazidime, piperacillin-tazobactam, and tetracycline were Tigecycline 0.5 2 100.0 0.0 0.0 89.7 10.3 0.0 50/90 50/90 inhibited at ≤4 mg/L), ceftazidime-nonsusceptible Enterobacter cloacae species Other Enterobacter spp. (102)f inhibited by ≤4 mg/L) and ceftazidime-nonsusceptible isolates of E. cloacae Acinetobacter baumannii calcoaceticus species complex (A. baumannii) 73.4%/73.4%, 74.5%/79.1%, 80.4%/85.0%, and —/60.1%, respectively Omadacycline 1 4 — — — — — — complex (E. cloacae, MIC50/90 2/8 mg/L; 88.5% inhibited at ≤4 mg/L), and Doxycycline 1 4 90.2 2.0 7.8 — — — (MIC50/90, 2/8 mg/L; 88.5% inhibited by ≤4 mg/L) isolates obtained in 2016 from European patients were associated with skin (Table 3) Tetracycline 1 4 90.2 1.0 8.8 — — — A.